This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIMS: In brain, axon growth or attenuated growth is guided by diverse receptors and ligands, designated axonal guidance molecules (AGMs), during neurodevelopment. In the adult brain, AGMs influence cognition (neurogenesis, synaptic plasticity, dendritic morphology) and pathological processes (promotion/blockade of axonal repair). Users of the drug methamphetamine (METH) are at high risk for addiction, neurotoxicity and cognitive impairment, manifest by pruning or losses in monoaminergic axons combined with impaired hippocampal function and neurogenesis. Based on our research that dopamine receptor activity can alter AGM mRNA expression, we investigated whether METH alters mRNA expression of AGMs in hippocampus, a brain region critical for learning, memory, neurogenesis. METHODS: We compared AGM mRNA expression in hippocampus of 5 control and 5 METH (5.0 mg/kg) treated mice, administered daily for 6, followed by a no treatment day. RESULTS: Real-time PCR detected robust mRNA expression of AGMs in adult whole mouse brain: semaphorin3e, semaphorin5a, neuropilin-1, ephrinA2, ephrinB3, EphB3, EphA4, EphB4, EphB6. mRNA expression levels of two AGMs (semaphorin5a and EphB3) were reduced in hippocampus of METH treated mice compared with saline controls. Semaphorin5a is an AGM implicated in axonal guidance and development of brain vasculature, and EphB3 is implicated in maintaining mature neuronal connections, re-arrangement of synaptic connections, and in hippocampal axon defasciculation. CONCLUSIONS: METH may alter hippocampal morphology and function by changing expression levels of axonal guidance molecules. Conceivably, AGMs contribute to METH-induced neurotoxicity and reduced cognition, thereby highlighting new mechanisms of METH action and leads for medications development.